Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies
Abstract
Jing LI1, Yun DU1, Xian LIU1, Qian-cheng SHEN1, Ai-long HUANG2, *, Ming-yue ZHENG1, *, Xiao-min LUO1, Hua-liang JIANG1
1Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
Aim: To investigate the molecular mechanisms underlying the influence of DNA polymerase from different genotypes of hepatitis B virus (HBV) on the binding affinity of adefovir (ADV).
Methods: Computational approaches, including homology modeling, docking, MD simulation and MM/PBSA free energy analyses were used.
Results: Sequence analyses revealed that residue 238 near the binding pocket was not only a polymorphic site but also a genotype-specific site (His238 in genotype B; Asn238 in genotype C). The calculated binding free-energy supported the hypothesis that the polymerase from HBV genotype C was more sensitive to ADV than that from genotype B. By using MD simulation trajectory analysis, binding free energy decomposition and alanine scanning, some energy variation in the residues around the binding pocket was observed. Both the alanine mutations at residues 236 and 238 led to an increase of the energy difference between genotypes C and B (ΔΔGC–B), suggesting that these residues contributed to the genotype-associated antiviral variability with regard to the interaction with ADV.
Conclusion: The results support the hypothesis that the HBV genotype C polymerase is more sensitive to ADV than that from genotype B. Moreover, residue N236 and the polymorphic site 238 play important roles in contributing to the higher sensitivity of genotype C over B in the interaction with ADV.
Keywords: hepatitis; HBV; polymerase; genotype; adefovir; molecular dynamics simulation; free energy calculation
This work is supported by the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. The authors gratefully acknowledge financial support from the State Key Program of Basic Research of China (No 2009CB918502), and the National Natural Science Foundation of China (No 81001399).
* To whom correspondence should be addressed.
E-mailahuang1964@163.com (Ai-long HUANG); myzheng@mail.shcnc.ac.cn (Ming-yue ZHENG)
Received 2012-04-24 Accepted 2012-09-24
Keywords:
1Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
Aim: To investigate the molecular mechanisms underlying the influence of DNA polymerase from different genotypes of hepatitis B virus (HBV) on the binding affinity of adefovir (ADV).
Methods: Computational approaches, including homology modeling, docking, MD simulation and MM/PBSA free energy analyses were used.
Results: Sequence analyses revealed that residue 238 near the binding pocket was not only a polymorphic site but also a genotype-specific site (His238 in genotype B; Asn238 in genotype C). The calculated binding free-energy supported the hypothesis that the polymerase from HBV genotype C was more sensitive to ADV than that from genotype B. By using MD simulation trajectory analysis, binding free energy decomposition and alanine scanning, some energy variation in the residues around the binding pocket was observed. Both the alanine mutations at residues 236 and 238 led to an increase of the energy difference between genotypes C and B (ΔΔGC–B), suggesting that these residues contributed to the genotype-associated antiviral variability with regard to the interaction with ADV.
Conclusion: The results support the hypothesis that the HBV genotype C polymerase is more sensitive to ADV than that from genotype B. Moreover, residue N236 and the polymorphic site 238 play important roles in contributing to the higher sensitivity of genotype C over B in the interaction with ADV.
Keywords: hepatitis; HBV; polymerase; genotype; adefovir; molecular dynamics simulation; free energy calculation
This work is supported by the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. The authors gratefully acknowledge financial support from the State Key Program of Basic Research of China (No 2009CB918502), and the National Natural Science Foundation of China (No 81001399).
* To whom correspondence should be addressed.
E-mailahuang1964@163.com (Ai-long HUANG); myzheng@mail.shcnc.ac.cn (Ming-yue ZHENG)
Received 2012-04-24 Accepted 2012-09-24